Xanthine oxidase is an enzyme catalyzing the conversion of hypoxanthine to xanthine and further to uric acid in nucleic acid metabolism.
A xanthine oxidase inhibitor inhibits uric acid synthesis to reduce a level of uric acid in the blood with respect to the action of xanthine oxidase. That is, a xanthine oxidase inhibitor is effective as a therapeutic agent for hyperuricemia and various diseases caused by hyperuricemia. On the other hand, there are gouty arthritis and gouty tophus called gout as a clinical condition caused by a result of deposition of urate crystals after prolonged hyperuricemia. In addition, hyperuricemia is considered to be important as a factor of lifestyle diseases associated with obesity, hypertension, dyslipidemia and diabetes or metabolic syndromes, and recently, it has been clarified that hyperuricemia is a risk factor of renal damage, urinary calculi and cardiovascular diseases by epidemiological surveys (The Guideline Revising Committee of Japanese Society of Gout and Nucleic Acid Metabolism, ed., Guideline for the management of hyperuricemia and gout, second edition, Medical Review (2010)). In addition, a xanthine oxidase inhibitor is expected to be useful for the treatment of diseases associated with active oxygen species by inhibitory activity against the active oxygen species generation, for example, for the treatment of cardiovascular diseases through the vascular function-improving action (Circulation. 2006; 114: 2508-2516).
Allopurinol and febuxostat are clinically used as a therapeutic agent for hyperuricemia, but allopurinol has been reported to have a side effect such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic disorder and renal dysfunction (Nippon Rinsho, 2003; 61, Suppl. 1: 197-201).
As a compound having a xanthine oxidase inhibitory activity, for example, a 2-phenylthiazole derivative is reported (PTL 1 to 3).
On the other hand, in PTL 4 and 5, a dithiazole carboxylic acid derivative having a benzene ring in the center is reported. Further, in PTL 6 and 7, a biphenyl thiazole carboxylic acid derivative is reported.